Aminopyrrolidine sulfonamides as serine protease inhibitors

ABSTRACT

The present invention is directed to compounds useful as selective serine protease or dual-serine protease inhibitors, compositions thereof and methods for treating serine protease or dual-serine protease mediated disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional application Serial No.60/274,845, filed Mar. 9, 2001, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to certain novel compounds, methods forpreparing the compounds, compositions, intermediates and derivativesthereof and for treating serine protease mediated disorders. Moreparticularly, the aminopyrrolidine sulfonamide compounds of the presentinvention are selective serine protease or dual-serine proteaseinhibitors of Factor Xa and tryptase useful for treating serine proteaseor dual-serine protease mediated disorders.

BACKGROUND OF THE INVENTION

Thrombotic disorders are a major cause of mortality in industrializedcountries (Kaiser, Brigitte, Thrombin and Factor Xa Inhibitors, Drugs ofthe Future, 1998, 23(4), 423-436). Thrombin has been a target for thedevelopment of anticoagulation agents because it occupies a centralposition in the coagulation cascade (Kunitada, S., et al., Factor XaInhibitors, Current Pharmaceutical Design, 1996, 2, 531-542). SinceFactor Xa (FXa) is responsible for the formation of thrombin, a FXainhibitor has become an alternative strategy to selectively preventthrombin production and clot formation.

Like thrombin, FXa is a member of the serine protease superfamily. Inthe blood coagulation cascade, FXa links the intrinsic and extrinsicactivation pathways for the production of thrombin. In the intrinsicpathway, Factor IXa converts Factor X to FXa in the presence of FactorVIIIa, Ca²⁺ and phospholipid. In the extrinsic pathway, Factor VIIaconverts Factor X to FXa in the presence of tissue factor. Once formed,FXa binds to Factor Va on phospholipid surfaces in the presence of Ca⁺²ions to form the prothrombinase complex, which is responsible forconverting prothrombin to thrombin. Thrombin in turn converts fibrinogento fibrin, which ultimately results in the production of a fibrin clot.

Potential advantages for FXa inhibitors as anticoagulants stem from theinhibition of thrombin formation rather than inhibition of its catalyticactivity. For example, it is expected that thrombin-induced plateletactivation could still occur under FXa inhibition, thus minimizingbleeding risk. The thrombin/thrombomodulin complex downregulatesthrombin production, thus functioning as an endogenous anticoagulant. Ithas been postulated that FXa inhibition would supply sufficient thrombinfor this interaction, which might minimize the “thrombotic rebound”effect observed in the clinical use of direct thrombin inhibitors.

A comprehensive review of FXa inhibitors has recently appeared (Drugs ofthe Future 1999, 24(7), 771-787).

PCT application WO 96/10022 to Faull, et. al., describessulfonylpiperazine-derived FXa inhibitors of the formula:

PCT application WO 98/54164 to Tawada, et. al., describessulfonylpiperazine-derived FXa inhibitors of the formula:

Accordingly, it is an object of the invention to provideaminopyrrolidine sulfonamide-derived compounds that are serine proteaseinhibitors; in particular, selective serine protease or dual-serineprotease inhibitors of Factor Xa and tryptase. It is another object ofthe invention to provide a process for preparing aminopyrrolidinesulfonamide compounds, compositions, intermediates and derivativesthereof. It is a further object of the invention to provide methods fortreating serine protease or dual-serine protease mediated disorders.

SUMMARY OF THE INVENTION

This invention is directed to aminopyrrolidine sulfonamide compoundsselected from the group consisting of Formula (I) and Formula (II):

wherein

R₁, is selected from the group consisting of hydrogen, C₁₋₈alkyl,C₃₋₇cycloalkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl and R₄C(O)CH₂—; whereinaryl and heteroaryl are optionally substituted with one to twosubstituents independently selected from R₄;

R₂ is selected from the group consisting of hydrogen, hydroxy,C₁₋₈alkoxy, aryloxy and aryl(C₁₋₈)alkoxy; with the proviso that R₂ isbonded to the heterocyclyl ring by a single bond; alternatively, R₂ isoxo; with the proviso that R₂ is bonded to the heterocyclyl ring by adouble bond;

R₃ is selected from the group consisting of aryl, aryl(C₁₋₈)alkyl,aryl(C₂₋₈)alkenyl, heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl;wherein aryl and heteroaryl are optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, C₁₋₈alkyl, C₁₋₈alkoxy, amino, (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, trihalo(C₁₋₈)alkyl and trihalo(C₁₋₈)alkoxy;

R₄ is selected from the group consisting of hydroxy, amino, C₁₋₈alkyl,(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₁₋₈alkoxy, carboxy,carboxy(C₁₋₈)alkyl, carboxy(C₁₋₈)alkoxy, (carboxy)amino,(carboxy(C₁₋₄)alkyl)amino, (carboxyaryl)amino,(carboxyaryl(C₁₋₄)alkyl)amino, (carboxy(C₁₋₄)alkylaryl)amino, aryloxy,aryl(C₁₋₈)alkoxy, (aryl)amino, (aryl(C₁₋₄)alkyl)amino,(C₁₋₄alkylaryl)amino, (arylcarboxy)amino, di(aryl)amino,di(aryl(C₁₋₄)alkyl)amino, C₁₋₈alkoxycarbonyl,C₁₋₈alkoxycarbonyl(C₁₋₈)alkoxy, aminocarbonyl, (C₁₋₈alkyl)aminocarbonyl,(carboxy(C₁₋₈)alkyl)aminocarbonyl,(C₁₋₈alkoxycarbonyl(C₁₋₈)alkyl)aminocarbonyl and guanidino; and,

G is selected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₄alkyl, C₁₋₈alkoxy, aryl, aryloxy, aryl(C₁₋₈)alkyl, aryl(C₁₋₈)alkoxy,amino, carboxy, alkylaminocarbonyl, alkylcarbonylamino,trihalo(C₁₋₈)alkyl and trihalo(C₁₋₈)alkoxy;

and pharmaceutically acceptable salts thereof.

The aminopyrrolidine sulfonamide compounds of the present invention areselective serine protease or dual-serine protease inhibitors useful fortreating serine protease mediated disorders. An embodiment of theinvention includes compounds that are selective or dual-inhibitors ofFactor Xa and tryptase.

The present invention includes a method for preparing instant compounds,compositions, intermediates and derivatives thereof and a method fortreating selective serine protease or dual-serine protease mediateddisorders.

DETAILED DESCRIPTION OF THE INVENTION

An embodiment of the instant compounds are those wherein, preferably, R₁is selected from the group consisting of hydrogen, aryl(C₁₋₈)alkyl andheteroaryl(C₁₋₈)alkyl, wherein aryl, heteroaryl and the aryl andheteroaryl portion of arylalkyl and heteroarylalkyl are optionallysubstituted with a substituent selected from R₄. More preferably, R₁ isselected from the group consisting of hydrogen, benzyl, phenethyl,phenylpropyl and benzofurylmethyl, wherein phenyl, the phenyl portion ofbenzyl and the benzofuryl portion of benzofurylmethyl are optionallysubstituted with a substituent selected from R₄. Most preferably, R₁ isselected from the group consisting of hydrogen, benzyl, phenylpropyl andbenzofurylmethyl, wherein phenyl, the phenyl portion of benzyl and thebenzofuryl portion of benzofurylmethyl are optionally substituted with asubstituent selected from R₄.

An embodiment of the instant compounds also include those wherein,preferably, R₂ is hydrogen.

An embodiment of the instant compounds further includes those wherein,preferably, R₃ is aryl(C₂₋₈)alkenyl, wherein aryl is optionallysubstituted with one to three substituents independently selected fromhalogen. More preferably, R₃ is independently selected from the groupconsisting of phenethenylene and phenylpropenylene, wherein phenyl isoptionally substituted with one to three substituents independentlyselected from the group consisting of chlorine and fluorine. Mostpreferably, R₃ is phenethenylene, wherein phenyl is substituted with oneto three substituents selected from chlorine.

Embodiments of the instant compounds include those wherein, preferably,R₄ is selected from the group consisting of hydroxy, di(C₁₋₄alkyl)amino,C₁₋₈alkoxy, carboxy, carboxy(C₁₋₈)alkoxy, aryl(C₁₋₈)alkoxy,C₁₋₈alkoxycarbonyl, C18alkoxycarbonyl(C₁₋₈)alkoxy, aminocarbonyl,(C₁₋₈alkyl)aminocarbonyl, (carboxy(C₁₋₈)alkyl)aminocarbonyl andC₁₋₈alkoxycarbonyl(C₁₋₈)alkyl)aminocarbonyl.

More preferably, R₄ is selected from the group consisting of hydroxy,carboxy, carboxy(C₁₋₈)alkoxy, C₁₋₈alkoxycarbonyl,C₁₋₈alkoxycarbonyl(C₁₋₈)alkoxy, aminocarbonyl,(carboxy(C₁₋₈)alkyl)aminocarbonyl andC₁₋₈alkoxycarbonyl(C₁₋₈)alkyl)aminocarbonyl.

Most preferably, R₄ is selected from the group consisting of hydroxy,carboxy, carboxymethoxy, methoxycarbonyl, aminocarbonyl,(carboxymethylene)aminocarbonyl andmethoxycarbonylmethylene)aminocarbonyl.

Embodiments of the instant compounds also include those wherein,preferably, G is selected from the group consisting of hydrogen,halogen, hydroxy, C₁₋₄alkyl, C₁₋₈alkoxy, aryl, aryloxy, aryl(C₁₋₈)alkyl,aryl(C₁₋₈)alkoxy, amino and trihalo(C₁₋₈)alkyl. More preferably, G ishydrogen.

The compounds of the present invention are exemplified by a compound ofthe formula:

Wherein R₄ is selected from:

Cpd R₄ 2 4-OH; 3 4-CO₂CH₃; 4 3-CO₂CH₃; 5 4-CO₂H; 6 3-CO₂H; 7 3-OH; 83-OCH₂CO₂CH₃; 9 4-CONH₂; 10 4-CONHCH₂CO₂CH₃; 11 3-OCH₂CO₂H; 124-CONHCH₂CO₂H; 13 3-CONHCH₂CO₂CH₃; 14 3-CONHCH₂CO₂H; 15 3-CONH₂; 244-NHC(═NH)NH₂; or, 25 3-CO₂CH₃-4-OH;

and pharmaceutically acceptable salts thereof.

The compounds of the present invention are also exemplified by a poundof the formula:

wherein R₁ is:

Cpd R₁ 1 PhCH₂; 26 H; or, 27 2-benzofurylCH₂

and pharmaceutically acceptable salts thereof.

The compounds of the present invention are further exemplified by acompound of the formula:

wherein R₁ and R₃ are dependently selected from:

Cpd R₁ R₃ 16 PhCH₂ 4-ClPh(CH)₂; 17 4-(PhCH₂O)PhCH₂ 4-ClPh(CH)₂; 184-[(CH₃)₂N]PhCH₂ 4-ClPh(CH)₂; 19 4-(CH₃O)PhCH₂ 4-ClPh(CH)₂; 20 Ph(CH₂)₃4-ClPh(CH)₂; 21 4-CO₂HPhCH₂ 4-ClPh(CH)₂; 22 4-[CH₃OC(O)]PhCH₂4-ClPh(CH)₂; or, 23 PhCH₂ 7-CH₃O-2-naphthalenyl;

and pharmaceutically acceptable salts thereof.

The compounds of the present invention may also be present in the formof a pharmaceutically acceptable salt. The pharmaceutically acceptablesalt generally takes a form in which the basic nitrogen is protonatedwith an inorganic or organic acid. Representative organic or inorganicacids include hydrochloric, hydrobromic, hydriodic, perchloric,sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic,succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation followed byfractional crystallization and regeneration of the free base. Thecompounds may also be resolved by formation of diastereomeric esters oramides, followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Resonance forms for compounds of the present invention include thoseforms where an unsaturated bond may resonate between 2 or more atoms.For example, a guanidino group includes resonance forms represented bythe formulae: —NH—C(═NH)—NH₂ or —N═C(NH₂)—NH₂. It is to be understoodthat all such resonance forms are encompassed within the scope of thepresent invention.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

The term “alkyl” refers to straight and branched-chain alkyl radicalgroups; similarly, alkenyl and alkynyl radicals include straight andbranched chains having 2 to 8 carbon atoms or any number within thisrange; wherein one or two double or triple bonds are formed in the chainbetween adjacent members. The term “alkoxy” refers to O-alkyl groupswhere alkyl is as defined supra. The term “cycloalkyl” refers to acyclic alkyl ring of five to seven carbon atom members. Examples of suchcyclic alkyl rings include pentyl, hexyl or heptyl.

The term “heterocyclyl” refers to a saturated or partially unsaturatedring having five members of which at least one member is a N, O or Satom and which optionally contains one additional O atom or one, two orthree additional N atoms, a saturated or partially unsaturated ringhaving six members of which one, two or three members are a N atom, asaturated or partially unsaturated bicyclic ring having nine members ofwhich at least one member is a N, O or S atom and which optionallycontains one, two or three additional N atoms or a saturated orpartially unsaturated bicyclic ring having ten members of which one, twoor three members are a N atom. Examples include, and are not limited to,pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl or piperazinyl.

The term “aryl” refers to a single aromatic ring of six carbon membersor a bicyclic aromatic ring of ten carbon members. Examples of such arylrings include phenyl and naphthyl.

The term “heteroaryl” refers to an aromatic monocyclic ring systemcontaining five members of which at least one member is a N, O or S atomand which optionally contains one, two or three additional N atoms; anaromatic monocyclic ring having six members of which one, two or threemembers are a N atom; an aromatic bicyclic ring having nine members ofwhich at least one member is a N, O or S atom and which optionallycontains one, two or three additional N atoms; or, an aromatic bicyclicring having ten members of which one, two or three members are a N atom.Examples include, and are not limited to, furyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl,benzo[b]furyl, benzo[b]thienyl, quinolinyl, isoquinolinyl orquinazolinyl.

The term “carbonyl” as used herein refers to the organic radical linkinggroup: R—C(O)—R having a single carbon atom; the term “carboxy” as usedherein refers to the organic radical terminal group: R—C(O)OH.

The term “halogen” or “halo” shall include iodine, bromine, chlorine andfluorine.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., aryl(C₁-C₄)alkyl, di(C₁-C₄alkyl)amino) it shall be interpreted as including those limitationsgiven above for “alkyl” and “aryl.” Designated numbers of carbon atoms(e.g., C₁-C₆) shall refer independently to the number of carbon atoms inan alkyl or cycloalkyl moiety or to the alkyl portion of a largersubstituent in which alkyl appears as its prefix root.

The term “aryl(C₁₋₈)alkyl” or the coextensive term “arylalkyl” means analkyl group substituted at the terminal carbon with an aryl group (e.g.,benzyl, phenethyl). Similarly, the term “heteroaryl(C₁₋₈)alkyl” or thecoextensive term “heteroarylalkyl” means an alkyl group substituted atthe terminal carbon with a heteroaryl group. The term “aryl(C₁₋₈)alkoxy”or the coextensive term “arylalkoxy” indicates an alkoxy groupsubstituted at the terminal carbon with an aryl group (e.g., benzyloxy).

When a particular group is “substituted” (e.g., Phe, aryl, heteroaryl),that group may have one or more substituents, preferably from one tofive substituents, more preferably from one to three substituents, mostpreferably from one to two substituents, independently selected from thelist of substituents.

Under standard nomenclature rules used throughout this disclosure, theterminal portion of the designated side chain is described firstfollowed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁₋₆alkylamidoC₁₋₆alkyl” substituent refersto a group of the formula:

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

The aminopyrrolidine sulfonamide-derived compounds of the presentinvention are selective serine protease or dual-serine proteaseinhibitors; in particular, selective or dual-inhibitors of Factor Xa andtryptase useful for treating selective serine protease or dual-serineprotease mediated disorders.

Embodiments of the method of the present invention include a method fortreating or ameliorating a serine protease or dual-serine proteasemediated disorder in a subject in need thereof comprising administeringto the subject a therapeutically effective amount of an instant compoundor pharmaceutical composition thereof. The therapeutically effectiveamount of the compounds selected from the group consisting of Formula(I) and Formula (II) exemplified in such a method is from about 0.001mg/kg/day to about 300 mg/kg/day.

Embodiments of the present invention include the use of a compoundselected from the group consisting of Formula (I) and Formula (II) forthe preparation of a medicament for treating or ameliorating a serineprotease or dual-serine protease mediated disorder in a subject in needthereof.

In accordance with the methods of the present invention, an individualcompound of the present invention or a pharmaceutical compositionthereof can be administered separately at different times during thecourse of therapy or concurrently in divided or single combinationforms. The instant invention is therefore to be understood as embracingall such regimes of simultaneous or alternating treatment and the term“administering” is to be interpreted accordingly.

Embodiments of the present method include a compound or pharmaceuticalcomposition thereof advantageously co-administered in combination withother agents for treating or ameliorating a serine protease ordual-serine protease mediated disorder. For example, in the treatment ofthrombosis, a compound selected from the group consisting of Formula (I)and Formula (II) or pharmaceutical composition thereof may be used incombination with other agents.

The combination product comprises co-administration of a compoundselected from the group consisting of Formula (I) and Formula (II) orpharmaceutical composition thereof and an additional agent for treatingor ameliorating a serine protease or dual-serine protease mediateddisorder, the sequential administration of a compound selected from thegroup consisting of Formula (I) and Formula (II) or pharmaceuticalcomposition thereof and an additional agent for treating or amelioratinga serine protease or dual-serine protease mediated disorder,administration of a pharmaceutical composition containing a compoundselected from the group consisting of Formula (I) and Formula (II) orpharmaceutical composition thereof and an additional agent for treatingor ameliorating a serine protease or dual-serine protease mediateddisorder or the essentially simultaneous administration of a separatepharmaceutical composition containing a compound selected from the groupconsisting of Formula (I) and Formula (II) or pharmaceutical compositionthereof and a separate pharmaceutical composition containing anadditional agent for treating or ameliorating a serine protease ordual-serine protease mediated disorder.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or human,that is being sought by a researcher, veterinarian, medical doctor, orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

The ubiquitous nature of the Factor Xa and tryptase isoforms and theirimportant roles in physiology provide incentive to produce highlyselective Factor Xa and tryptase inhibitors. Given the evidencedemonstrating linkage of certain isoforms to disease states, it isreasonable to assume that inhibitory compounds that are selective to aserine protease isoform or to a Factor Xa isoform relative to the atryptase isoform and other serine proteases or dual-serine protease aresuperior therapeutic agents. Such compounds should demonstrate greaterefficacy and lower toxicity by virtue of their specificity. Accordingly,it will be appreciated by one skilled in the art that a compoundselected from the group consisting of Formula (I) and Formula (II) istherapeutically effective for certain serine protease or dual-serineprotease mediated disorders based on the modulation of the disorder byselective serine protease or dual-serine protease inhibition. Theusefulness of a compound selected from the group consisting of Formula(I) and Formula (II) as a selective serine protease or dual-serineprotease inhibitor can be determined according to the methods disclosedherein and the scope of such use includes use in one or more serineprotease or dual-serine protease mediated disorders.

More particularly, the term “serine protease or dual-serine proteasemediated disorders” includes, and is not limited to, thromboticdisorders, arterial thrombosis, venous thrombosis, restenosis,hypertension, heart failure, arrhythmia, myocardial infarction, acutemyocardial infarction, reocclusion following thrombolytic therapy,reocclusion following angioplasty, inflammation, angina, unstableangina, stroke, atherosclerosis, ischemic conditions, neurodegenerativedisorders (associated with thrombotic or ischemic conditions), asthmaand inflammatory bowel syndrome. Certain of the instant compounds arealso useful as antithrombotics and anticoagulation agents in conjunctionwith fibrinolytic therapy (e.g., t-PA or streptokinase). The utility ofthe compounds to treat serine protease or dual-serine protease mediateddisorders can be determined according to the procedures describedherein.

Additionally, compounds of the present invention (such as Compound 27)may be useful in treating a chronic neurodegenerative disorder (such asAlzheimer's disease) (tested for activity using methodology similar tothat described in Ermolieff, J., et al, Proteolytic Activation ofRecombinant Pro-memapsin 2 (Pro-β-secretase) Studied with NewFluorogenic Substrates, Biochemistry, 2000, 39,12450-12456).

The present invention further provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.Accordingly, pharmaceutical compositions containing the compounds of thepresent invention as the active ingredient as well as methods ofpreparing the instant compounds are also part of the present invention.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I), Formula (II) or salt thereof as theactive ingredient, is intimately admixed with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques, whichcarrier may take a wide variety of forms depending of the form ofpreparation desired for administration (e.g. oral or parenteral).Suitable pharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman,et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes1-2, edited by Avis, et al.; and Pharmaceutical Dosage Forms: DisperseSystems, Volumes 1-2, edited by Lieberman, et al.; published by MarcelDekker, Inc.

In preparing a pharmaceutical composition of the present invention inliquid dosage form for oral, topical and parenteral administration, anyof the usual pharmaceutical media or excipients may be employed. Thus,for liquid dosage forms, such as suspensions (i.e. colloids, emulsionsand dispersions) and solutions, suitable carriers and additives includebut are not limited to pharmaceutically acceptable wetting agents,dispersants, flocculation agents, thickeners, pH control agents (i.e.buffers), osmotic agents, coloring agents, flavors, fragrances,preservatives (i.e. to control microbial growth, etc.) and a liquidvehicle may be employed. Not all of the components listed above will berequired for each liquid dosage form.

In solid oral preparations such as, for example, powders, granules,capsules, caplets, gelcaps, pills and tablets (each including immediaterelease, timed release and sustained release formulations), suitablecarriers and additives include but are not limited to diluents,granulating agents, lubricants, binders, glidants, disintegrating agentsand the like. Because of their ease of administration, tablets andcapsules represent the most advantageous oral dosage unit form, in whichcase solid pharmaceutical carriers are obviously employed. If desired,tablets may be sugar coated, gelatin coated, film coated or entericcoated by standard techniques.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful and the like, anamount of the active ingredient necessary to deliver an effective doseas described above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01 mg to about300 mg (preferably, from about 0.1 mg to about 100 mg; and, morepreferably, from about 1 mg to about 30 mg) and may be given at a dosageof from about 0.01 mg/kg/day to about 300 mg/kg/day (preferably, fromabout 0.1 mg/kg/day to about 100 mg/kg/day; and, more preferably, fromabout 1 mg/kg/day to about 30 mg/kg/day). Preferably, in the method fortreating thrombotic disorders described in the present invention andusing any of the compounds as defined herein, the dosage form willcontain a pharmaceutically acceptable carrier containing between about0.01 mg and 100 mg; and, more preferably, between about 5 mg and 50 mgof the compound; and, may be constituted into any form suitable for themode of administration selected. The dosages, however, may be varieddepending upon the requirement of the subjects, the severity of thecondition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms such as tablets,pills, capsules, powders, granules, lozenges, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories for administration byoral, intranasal, sublingual, intraocular, transdermal, parenteral,rectal, vaginal, inhalation or insufflation means. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection.

For preparing solid pharmaceutical compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and glidants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethycellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable glidants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W.R. Grace/Davison, and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c)dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate such as celluloseacetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, methacrylate and ethylacrylate copolymers, methacrylate andmethyl methacrylate copolymers and the like. Sustained release tabletsmay also be made by film coating or wet granulation using slightlysoluble or insoluble substances in solution (which for a wet granulationacts as the binding agents) or low melting solids a molten form (whichin a wet granulation may incorporate the active ingredient). Thesematerials include natural and synthetic polymers waxes, hydrogenatedoils, fatty acids and alcohols (i.e. beeswax, carnauba wax, cetylalcohol, cetylstearyl alcohol, and the like), esters of fatty acidsmetallic soaps, and other acceptable materials that can be used togranulate, coat, entrap or otherwise limit the solubility of an activeingredient to achieve a prolonged or sustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agent include pharmaceutical gradelecithins. Suitable flocculating agent include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms, however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include, but are not limited to polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, tohomopolymers and copolymers (which means polymers containing two or morechemically distinguishable repeating units) of lactide (which includeslactic acid d-, I- and meso lactide), glycolide (including glycolicacid), ε-caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylenecarbonate (1,3-dioxan-2-one), alkyl derivatives of trimethylenecarbonate, δ-valerolactone, β-butyrolactone, γ-butyrolactone,ε-decalactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxepan-2-one(including its dimer 1,5,8,12-tetraoxacyclotetradecane-7,14-dione),1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels and blends thereof.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever treatment of serineprotease or dual-serine protease mediated disorders is required for asubject in need thereof.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.7 mg to about 21,000 mg per70 kilogram (kg) adult human per day; preferably in the range of fromabout 0.7 mg to about 7,000 mg per adult human per day; and, morepreferably, in the range of from about 0.7 mg to about 2,100 mg peradult human per day. For oral administration, the compositions arepreferably provided in the form of tablets containing, 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the subject to be treated. A therapeutically effectiveamount of the drug is ordinarily supplied at a dosage level of fromabout 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably,the range is from about 0.1 mg/kg to about 100 mg/kg of body weight perday; and, most preferably, from about 1 mg/kg to about 30 mg/kg of bodyweight per day. Advantageously, compounds of the present invention maybe administered in a single daily dose or the total daily dosage may beadministered in divided doses of two, three or four times daily.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, and theadvancement of the disease condition. In addition, factors associatedwith the particular subject being treated, including subject age,weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level.

In the examples and throughout this application, the followingabbreviations have the meanings recited hereinafter:

Boc t-Butoxycarbonyl Cpd or Cpmd Compound DCC1,3-Dicyclohexylcarbodiimide DIPEA Diisopropylethylamine DMFN,N-Dimethylformamide EtOAc Ethyl acetate h Hour KHSO₄ Potassiumbisulfate MeOH Methanol min Minute mL Milliliter NaBH₄ Sodiumborohydride Na₂SO₄ Sodium sulfate NaHCO₃ Sodium bicarbonate rt roomtemperature TFA Trifluoroacetic acid

General Synthetic Examples

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

The following scheme describes general synthetic methods wherebyintermediate and target compounds of the present invention may beprepared. Additional representative compounds of the present inventioncan be synthesized using the intermediates prepared in accordance withthe schemes and other materials, compounds and reagents known to thoseskilled in the art.

General Synthetic Examples

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

The following scheme describes general synthetic methods wherebyintermediate and target compounds of the present invention may beprepared. Additional representative compounds of the present inventioncan be synthesized using the intermediates prepared in accordance withthe schemes and other materials, compounds and reagents known to thoseskilled in the art.

Scheme A illustrates a general synthetic route for compounds of Formula(I).

In a modification of a known procedure (Syn. Comm. 1992, 22(19) 2357),the 3-aminopyrrolidine Compound A1 was treated with an aldehyde in asolvent such as toluene and the mixture was heated at reflux with waterremoval by a Dean-Stark apparatus. The required pyrrolidine intermediatefor preparing compounds wherein R₂ is oxo may be made according to PCTapplication WO 98/05336. The required intermediate for compounds whereinR₁ is H may be made by using a commercially available3-buytyloxycarbonylamino pyrrolidine or other known analog. Upon coolingto rt, the solution was treated with a protecting group reagent such asdi-tert-butyl dicarbonate. The intermediate imine was dissolved in ananhydrous solvent such as methanol and treated with a reducing agentsuch as NaBH₄ to afford an amine Compound A2. Treatment of Compound A2with an acid chloride such as 4-nitrobenzoyl chloride in a solvent suchas CH₂Cl₂ followed by solvent removal and treatment with TFA affordedCompound A3.

Sulfonylation of Compound A3 can be carried out by treating Compound A3with a sulfonyl halide in a solvent such as CH₂Cl₂ in the presence of anamine base such as DIPEA to afford Compound A4.

Treatment of Compound A4 with a reducing agent such as SnCl₂ in thepresence of a mineral acid such as HCl in an alcoholic solvent such asMeOH afforded Compound A5.

Guanylation of Compound A5 was carried out by treating Compound A5 witha guanylating agent such N,N′-bis-tert-butoxycarbonylthiourea in thepresence of HgCl₂, an amine base such as triethylamine in a solvent suchas DMF to afford Compound A6. Treatment of Compound A6 withtrifluoroacetic acid yielded the target compound of Formula (I).

Scheme B illustrates the general synthetic route for compounds ofFormula (11).

The intermediate Compound A2 (Scheme A) was treated with a sulfonylhalide in a solvent such as CH₂Cl₂ in the presence of an amine base suchas DIPEA to afford Compound B1. Treatment of Compound B1 with TFA in asolvent such as CH₂Cl₂ gave Compound B2. A mixture of Compound B2, anaromatic carboxylic acid chloride such as 4-nitrobenzoyl chloride and abase such as DIPEA in a solvent such as CH₂Cl₂ were stirred at rt toafford Compound B3.

Treatment of Compound B3 with a reducing agent such as SnCl₂ in thepresence of a mineral acid such as HCl in an alcoholic solvent such asMeOH afforded Compound B4.

Guanylation of Compound B4 was carried out by treating Compound B4 witha guanylating agent such N,N′-bis-tert-butoxycarbonythiourea in thepresence of HgCl₂ and an amine base such as triethylamine in a solventsuch as DMF to afford Compound B5. Treatment of Compound B5 withtrifluoroacetic acid in a solvent such as CH₂Cl₂ yielded the targetcompound of Formula (II).

SPECIFIC SYNTHETIC EXAMPLES

Specific compounds which are representative of this invention wereprepared as per the following examples and reaction sequences; theexamples and the diagrams depicting the reaction sequences are offeredby way of illustration, to aid in the understanding of the invention andshould not be construed to limit in any way the invention set forth inthe claims which follow thereafter. The depicted intermediates may alsobe used in subsequent examples to produce additional compounds of thepresent invention. No attempt has been made to optimize the yieldsobtained in any of the reactions. One skilled in the art would know howto increase such yields through routine variations in reaction times,temperatures, solvents and/or reagents.

All chemicals were obtained from commercial suppliers and used withoutfurther purification. ¹H and ¹³C NMR spectra were recorded on a BrukerAC 300B (300 MHz proton)or a Bruker AM-400 (400 MHz proton) spectrometerwith Me₄Si as an internal standard (s=singlet, d=doublet, t=triplet,broad). APCI-MS and ES-MS were recorded on a VG Platform II massspectrometer. TLC was performed with Whatman 250-μm silica gel plates.Preparative TLC was performed with Analtech 1000-μm silica gel GFplates. Flash column chromatography was conducted with flash columnsilica gel (40-63 μm) and column chromatography was conducted withstandard silica gel. HPLC separations were carried out on three WatersPrepPak® Cartridges (25×100 mm, Bondapak® C18, 15-20 μm, 125 Å)connected in series; detection was at 254 nm on a Waters 486 UVdetector. Analytical HPLC was carried out on a Supelcosil ABZ+PLUScolumn (5 cm×2.1 mm), with detection at 254 nm on a Hewlett Packard 1100UV detector. Microanalysis was performed by Robertson MicrolitLaboratories, Inc.

Representative Chemical Abstracts Service (CAS) Index-like names for thecompounds of the present invention were derived using the ACD/LABSSOFTWARE™ Index Name Pro Version 4.5 nomenclature software programprovided by Advanced Chemistry Development, Inc., Toronto, Ontario,Canada.

Example 14-[[[1-[[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl]-3-pyrrolidinyl][4-[(diaminomethylene)amino]benzoyl]amino]methyl]-benzoicAcid (Compound 5)

To a solution of Compound 1A (1.4 g, 16.0 mMol) in toluene (65 mL) wasadded methyl 4-formyl benzoate (2.6 g, 16.0 mMol). The reaction wasrefluxed (Dean-Stark trap) until water distillation ended (˜30 min). Thesolution was cooled to rt and treated with di-tert-butyl dicarbonate(3.1 g, 16.0 mMol) in one portion. After stirring overnight, thereaction was concentrated to yield Compound 1B as a yellow-brown oil: ¹HNMR (CDCl₃) δ 1.37-1.58 (m, 9H), 1.71-2.22 (overlapping m, 3H),3.32-3.73 (overlapping m, 4H), 3.88-4.09 (overlapping m, 4H), 7.71 (d,2H), 8.09 (d, 2H), 8.37 (s, 1H) ppm.

To a solution of Compound 1B at 0° C. in 50 mL of MeOH was added excessNaBH₄ (0.8 g, 21.1 mMol). The ice bath was removed and the solution waswarmed to rt. To the solution was added 3 mL of acetone, and thesolution was concentrated to yield a gummy solid which was partitionedbetween EtOAc and brine. The layers were separated and the aqueous layerwas extracted with EtOAc. The combined extracts were filtered and driedover Na₂SO₄. The solution was filtered through Celite and concentratedto yield Compound 1C as an orange oil: 5.5 g; HPLC: 2.42 min, 100%;ES-MS 335(MH⁺); ¹H NMR (CDCl₃) δ 1.48 (s, 9H), 1.66-1.81 (m, 1H),1.98-2.11 (m, 1H), 3.04-3.22 (m, 1H), 3.26-3.62 (overlapping m, 4H),3.87 (s, 2H), 3.92 (s, 3H), 7.4 (d, 2H), 8.0 (d, 2H).

To a solution of Compound 1C (1.1 g, 3.4 mMol) in CH₂Cl₂ (30 mL) wasadded DIPEA (0.6 mL, 3.4 mMol) followed by p-nitrobenzoyl chloride (0.6g, 3.4 mMol). After 40 min, the reaction was concentrated and theresidue was treated with 25 mL of TFA and stirred for 25 min. Thesolution was concentrated to yield Compound 1D as an orange oil: HPLC2.55 min, 91%; ES-MS 384 (MH⁺).

To a solution of Compound 1D in CH₂Cl₂ (30 mL) was added DIPEA (6.5 mL,37.3 mMol) followed by 0.9 g, 3.7 mMol) of p-chloroistyrylsulfonylchloride (prepared as in WO 96/10022) and stirred for 30 min. Thereaction solution was washed sequentially with 2× 1N KHSO₄, 2× sat.NaHCO₃, 1× brine, and filtered. The filtrate was dried over Na₂SO₄,filtered through Celite, and concentrated to yield Compound 1E as abrown foam: 2.0 g; HPLC 4.04 min, 85%.

To a suspension of Compound 1E (1.8 g, 3.1 mMol) in MeOH (40 mL) wasadded a solution of SnCl₂ (2.9 g, 15.4 mMol) in concentrated HCl (10 mL)and refluxed for 1.5h. The solution was concentrated, made basic (bluelitmus) 1N NaOH and extracted twice with EtOAc. The combined extractswere washed with brine, dried over Na₂SO₄, filtered and concentrated toyield 1.5 g of Compound 1F as a yellow glass:; HPLC 3.38 min, 81%.

To a solution of Compound 1F (1.6 g, 2.9 mMol) in DMF (30 mL) was added(1.2 g, 4.4 mMol) of N,N′-bis-tert-butoxycarbonylthiourea (Syn. Comm.1993, 23(10), 1443. ) followed by TEA (1.4 mL, 9.7 mMol). To thesolution was added 1.2 g (4.4 mMol) of HgCl₂. After 5 h, the blackreaction mixture was diluted with EtOAc (150 mL) and filtered throughCelite. The resulting light orange solution was washed sequentially withwater and brine, filtered, dried over Na₂SO₄ and concentrated. Theresidue was purified by flash column chromatography (silica gel,CH₂Cl₂:MeOH; 100%→99:1) to yield Compound 1G as a white solid: (0.9 g,38.5%); HPLC 99% 4.48 min; ES-MS 796 (MH⁺).

To a solution of Compound 1G (0.1 g, 0.1 mMol) in 1,4-dioxane (18 mL)was added a solution of LiOH.H₂O (16 mg, 0.4 mMol) in H₂O (2 mL) andstirred overnight. The reaction solution was concentrated, acidifiedwith excess 1N KHSO₄, and extracted three times with EtOAc. The combinedextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography(silica gel, 98:2 CH₂Cl₂:MeOH) to afford Compound 1H as a white powder:(48 mg, 51%); HPLC 4.25 min; 99%.

A solution of Compound 1H (48 mg, 0.06 mMol) was dissolved in 2 mL ofTFA and stirred for 30 min. The solution was concentrated to yield aclear oil which was triturated 2× Et₂O and dried under vacuum at rt toyield Compound 5 as a white solid: (37.0 mg, 85%); HPLC 2.76 min, 100%.ES-MS 582 (MH⁺); ¹H NMR (DMSO-d₆) δ 1.88-2.12 (broad s, 2H), 2.92-3.53(overlapping m, 4H), 4.38-4.58 (overlapping m, 3H), 7.07-7.98 (m, 18H),9.98 (broad s,1H).

Using the procedure of Example 1 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe 5 present invention may be prepared including, but not limited to:

ES-MS Cpd Name m/z (MH⁺) 1N-[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 538pyrrolidinyl]-4-[(diaminomethylene)amino]-N- (phenylmethyl)-benzamide 2N-[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 554pyrrolidinyl]-4-[(diaminomethylene)amino]-N-[(4-hydroxyphenyl)methyl]-benzamide 34-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 596pyrrolidinyl][4-[(diaminomethylene)amino]- benzoyl]amino]methyl]-benzoicacid methyl ester 4 3-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3-596 pyrrolidinyl][4-[(diaminomethylene)amino]-benzoyl]amino]methyl]-benzoic acid methyl ester 63-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 582pyrrolidinyl][4-[(diaminomethylene)amino]- benzoyl]amino]methyl]-benzoicacid 7 N-[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 554pyrrolidinyl]-4-[(diaminomethylene)amino]-N-[(3-hydroxyphenyl)methyl]-benzamide 8[3-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 626pyrrolidinyl][4-[(diaminomethylene)amino]-benzoyl]amino]methyl]phenoxy]-acetic acid methyl ester 9N-[[4-(aminocarbonyl)phenyl]methyl]-N-[1-[[(E)-2- 581(4-chlorophenyl)ethenyl]sulfonyl]-3-pyrrolidinyl]-4-[(diaminomethylene)amino]-benzamide, 10[[4-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 653pyrrolidinyl][4-[(diaminomethylene)amino]benzoyl]-amino]methyl]benzoyl]amino]-acetic acid methyl ester 11[3-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 612pyrrolidinyl][4-[(diaminomethylene)amino]benzoyl]-amino]methyl]phenoxy]-acetic acid 12[[4-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 639pyrrolidinyl][4-[(diaminomethylene)amino]benzoyl]-amino]methyl]benzoyl]amino]-acetic acid 13[[3-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 653pyrrolidinyl][4-[(diaminomethylene)amino]benzoyl]-amino]methyl]benzoyl]amino]-acetic acid methyl ester 14[[3-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 639pyrrolidinyl][4-[(diaminomethylene)amino]-benzoyl]amino]methyl]benzoyl]amino]-acetic acid 153-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 581pyrrolidinyl][4-[(diaminomethylene)amino]-benzoyl]amino]methyl]-benzamide 24N-[[4-[(aminoiminomethyl)amino]phenyl] methyl]- 595N-[1-[[(E)-2-(4-chlorophenyl)ethenyl]-sulfonyl]-3-pyrrolidinyl]-4-[(diaminomethylene)- amino]-benzamide 255-[[[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 612pyrrolidinyl][4-[(diaminomethylene)amino]-benzoyl]amino]methyl]-2-hydroxy-benzoic acid methyl ester 26N-[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- 448pyrrolidinyl]-4-[(diaminomethylene)amino]- benzamide 274-[(aminoiminomethyl)amino]-N- 578 (2-benzofuranylmethyl)-N-[1-[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl]-3- pyrrolidinyl]-benzamide

Example 24-[[[[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl][1-[4-[(diaminomethylene)amino]benzoyl]-3-pyrrolidinyl]amino]methyl]-benzoicAcid (Compound 21)

To solution of Compound 1C (prepared in Example 1; 0.90 g, 2.7 mMol) inCH₂CL₂ (30 mL) was added DIPEA (0.5 mL, 2.7 mMol) followed byp-chlorostyrylsulfonyl chloridel (0.7 g, 2.7 mMol) and stirred at rtovernight. The reaction was cooled to rt and washed sequentially with 1NKHSO₄ and brine. The combined extracts were dried (Na₂SO₄), filtered andconcentrated to afford Compound 2A as an orange foam: HPLC 4.31 min;86%. Compound 2A was treated with 20 mL of TFA and stirred for 3.25 h.The solution was concentrated to afford Compound 2B as a brown oil: 2.3g. To a solution of Compound 2B in CH₂Cl₂ (30 mL) was added DIPEA (2.0mL, 11.5 mMol) followed by p-nitrobenzoyl chloride (0.4 g, 2.3 mMol) andstirred for 1 h. The solution was washed sequentially with 1N HCl, H₂O,1N NaOH, and brine, then dried (Na₂SO₄), filtered and concentrated toyield Compound 2C: 1.5 g; HPLC: 4.0 min, 75%.

To a suspension of Compound 2C (1.5 g, 2.5 mMol) in MeOH (30 mL) wasadded SnCl₂ (2.4 g, 12.7 mMol) dissolved in conc. HCl (15 mL) and theresulting suspension heated to reflux. After 30 min at reflux, thereaction was cooled to rt, concentrated, and made basic with 1N NaOH.The mixture wasextracted twice with EtOAc, and the combined extractswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash column chromatography (Biotage Flash 40 column, IscoUA-6 gradient pump; CH₂Cl₂:MeOH; 98:2→94:6) to yield Compound 2D as anoff white solid: (0.4 g, 31%); HPLC 3.34 min, 100%; ES-MS 595 (MH⁺).

A solution of Compound 2D (0.4 g, 0.8 mMol) andN,N′-bis-tert-butoxycarbonylthiourea (Syn. Comm. 1993, 23(10), 1443; 0.3g, 1.2 mMol) in 15 mL of DMF was treated with TEA (0.4mL, 2.6 mMol)followed by HgCl₂ (1.8 mMol, 0.5 g) and the reaction was stirredovernight. The black suspension was diluted with EtOAc (150 mL) andfiltered through Celite. The filtrate was washed sequentially with H₂Oand brine, filtered, dried (Na₂SO₄), and concentrated. The residue waspurified by flash column chromatography (Biotage Flash 40 column, lscoUA-6 gradient pump; CH₂Cl₂:MeOH; 100%→96:4) to yield Compound 2E as awhite solid: (0.5 g, 73%); HPLC 4.51 min, 100%.

To a solution of Compound 2E (0.4 g, 0.5 mMol) in 1,4-dioxane (18 mL)was added a solution of LiOH.H₂O (58 mg, 1.4 mMol) in H₂O (2 mL) andstirred for 48 hr. The solution was concentrated, acidified with 1 NKHSO₄, and extracted twice with EtOAc. The combined extracts were washedwith brine, dried over Na₂SO₄, filtered through Celite and concentrated.The residue was purified by flash column chromatography (Biotage Flash40 column, lsco UA-6 gradient pump; CH₂Cl₂:MeOH; 100%→94:6) to yieldCompound 2F as a white powder: (0.2 g, 33%); HPLC: 4.31 min, 100%.

A solution of Compound 2F (63 mg, 0.08 mMol) in 2 mL of 100% TFA wasstirred for 45 min. The solution was concentrated to yield a clear oilwhich was triturated twice with Et₂O and dried under vacuum at rt toyield Compound 21 as a white solid: (43 mg, 77%); HPLC: 3.0 min 94%;ES-MS 582 (MH⁺); ¹H NMR (DMSO-d₆) 61.75-2.13 (m, 2H), 3.12-3.79(overlapping m, 4H), 4.31-4.68 (overlapping m, 3H), 7.08-8.11(overlapping m, 18H), 10.0 (broad s, 1H).

Using the procedure of Example 2 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS Cpd Name m/z (MH⁺) 16 2-(4-chlorophenyl)-N-[1-[4- 538[(diaminomethylene)amino]benzoyl]-3-pyrrolidinyl]-N-(phenylmethyl)-(E)-ethenesulfonamide 17 2-(4-chlorophenyl)-N-[1-[4-645 [(diaminomethylene)amino]benzoyl]-3-pyrrolidinyl]-N-[[4-(phenylmethoxy)phenyl]methyl]-(E)- ethenesulfonamide 182-(4-chlorophenyl)-N-[1-[4- 582[(diaminomethylene)amino]benzoyl]-3-pyrrolidinyl]-N-[[4-(dimethylamino)phenyl]methyl]-(E)- ethenesulfonamide 192-(4-chlorophenyl)-N-[1-[4- 569[(diaminomethylene)amino]benzoyl]-3-pyrrolidinyl]-N-[(4-methoxyphenyl)methyl]-(E)- ethenesulfonamide 202-(4-chlorophenyl)-N-[1-[4- 567[(diaminomethylene)amino]benzoyl]-3-pyrrolidinyl]-N-(3-phenylpropyl)-(E)-ethenesulfonamide 224-[[[[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl][1-[4- 596[(diaminomethylene)amino]benzoyl]-3- pyrrolidinyl]amino]methyl]-benzoicacid methyl ester 23 N-[1-[4-[(diaminomethylene)amino]benzoyl]-3- 558pyrrolidinyl]-7-methoxy-N-(phenylmethyl)-2- naphthalenesulfonamide

Biological Examples

The utility of the compounds of the present invention as serine proteaseor dual-serine protease inhibitors and, particularly, as Factor Xa ortryptase inhibitors useful as agents for the treatment of serineprotease or dual-serine protease mediated disorders can be determinedaccording to the procedures described herein.

Enzyme-Catalyzed Hydrolysis Assays

Factor Xa Inhibition

Enzyme-catalyzed hydrolysis rates were measured spectrophotometricallyusing commercial human Factor Xa (American Diagnostica), the chromogenicsubstrate (MeO-CO-D-CHG-Gly-Arg-pNa (American Diagnostica); in aqueousbuffer (50 mM Trisma Base, 0.1% Tween 80, pH 8.4), and a microplatereader (Molecular Devices). Changes in absorbance at 405 nM weremonitored using the software program Softmax (Molecular Devices), uponaddition of enzyme, with and without inhibitor present at 37° C. for 30minutes. The IC₅₀ values were determined by fixing the enzyme andsubstrate concentrations (5.7 nM Factor Xa, 500 μM Factor Xa substrate)and varying the inhibitor concentration. Percent inhibition wascalculated by comparing the initial reaction slopes of the withoutinhibitor samples to those with inhibitor. Inhibition constants (K_(i))were determined by fixing the enzyme concentrations (5.7 nM Factor Xa)and inhibitor concentrations and varying the substrate concentrations(30-700 μM Factor Xa substrate. Michaelis-Menton kinetics were appliedto the initial reaction slopes using the program Kcat (Bio MetallicsInc.).

Table 1summarizes assay results for Factor Xa inhibition for certaincompounds of the present invention:

TABLE 1 Factor Xa K_(i) Cpd (μM) 1 1.6 2 0.3 3 0.4 4 7.7 5 0.2 6 0.6 70.3 8 1.1 9 0.3 10 0.2 11 0.6 12 0.4 13 0.2 14 0.3 15 0.6 17 4.4 22 7.123 21 27 0.1

Tryptase Inhibition

The rate of increase in absorbance at 405 nM due to hydrolysis ofsynthetic chromogenic peptide substrates ([S]: 500 μMN-p-Tosyl-GLY-PRO-LYS-pNA; Sigma T-6140) is measured in the presence andabsence of inhibitors (I) with a microplate reader at 37° C. The enzymereaction is started by the addition of enzyme ([E]: 1.0 nM human LungTryptase; Cortex Biochem CP3033). Data is collected over a period of 30min. and the initial rate of substrate hydrolysis (Vo (mOD/min)) iscalculated. Inhibition is calculated by comparing to wells containing noinhibitor (vehicle) and lC₅₀s are determined using a four parameter fitlogistics model.

Table 2 summarizes assay results for tryptase inhibition for certaincompounds of the present invention:

TABLE 2 Cpd Tryptase IC₅₀ (μM) 2 0.9 24 4.0 25 0.7 26 0.6

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

What is claimed is:
 1. A compound selected from the group consisting ofFormula (I) and Formula (II):

wherein R₁ is selected from the group consisting of hydrogen, C₁₋₈alkyl,C₃₋₇cycloalkyl, aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl and R₄C(O)CH₂—; whereinaryl and heteroaryl are optionally substituted with one to twosubstituents independently selected from R₄; R₂ is selected from thegroup consisting of hydrogen, hydroxy, C₁₋₈alkoxy, aryloxy andaryl(C₁₋₈)alkoxy; with the proviso that R₂ is bonded to the heterocyclylring by a single bond; alternatively, R₂ is oxo; with the proviso thatR₂ is bonded to the heterocyclyl ring by a double bond; R₃ is selectedfrom the group consisting of aryl, aryl(C₁₋₈)alkyl, aryl(C₂₋₈)alkenyl,heteroaryl(C₁₋₈)alkyl, heteroaryl(C₂₋₈)alkenyl; wherein aryl andheteroaryl are optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, C₁₋₈alkyl,C₁₋₈alkoxy, amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino,trihalo(C₁₋₈)alkyl and trihalo(C₁₋₈)alkoxy; R₄ is selected from thegroup consisting of hydroxy, amino, C₁₋₈alkyl, (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, C₁₋₈alkoxy, carboxy, carboxy(C₁₋₈)alkyl,carboxy(C₁₋₈)alkoxy, (carboxy)amino, (carboxy(C₁₋₄)alkyl)amino,(carboxyaryl)amino, (carboxyaryl(C₁₋₄)alkyl)amino,(carboxy(C₁₋₄)alkylaryl)amino, aryloxy, aryl(C₁₋₈)alkoxy, (aryl)amino,(aryl(C₁₋₄)alkyl)amino, (C₁₋₄alkylaryl)amino, (arylcarboxy)amino,di(aryl)amino, di(aryl(C₁₋₄)alkyl)amino, C₁₋₈alkoxycarbonyl,C₁₋₈alkoxycarbonyl(C₁₋₈)alkoxy, aminocarbonyl, (C₁₋₈alkyl)aminocarbonyl,(carboxy(C₁₋₈)alkyl)aminocarbonyl,(C₁₋₈alkoxycarbonyl(C₁₋₈)alkyl)aminocarbonyl and guanidino; and, G isselected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₄alkyl, C₁₋₈alkoxy, aryl, aryloxy, aryl(C₁₋₈)alkyl, aryl(C₁₋₈)alkoxy,amino, carboxy, alkylaminocarbonyl, alkylcarbonylamino,trihalo(C₁₋₈)alkyl and trihalo(C₁₋₈)alkoxy; and pharmaceuticallyacceptable salts thereof.
 2. The compound of claim 1 wherein R₁ isselected from the group consisting of hydrogen, aryl(C₁₋₈)alkyl andheteroaryl(C₁₋₈)alkyl, wherein the aryl and heteroaryl portion ofarylalkyl and heteroarylalkyl are optionally substituted with asubstituent selected from R₄.
 3. The compound of claim 1 wherein R₁ isselected from the group consisting of hydrogen, benzyl, phenethyl,phenylpropyl and benzofurylmethyl, wherein phenyl, the phenyl portion ofbenzyl and the benzofuryl portion of benzofurylmethyl are optionallysubstituted with a substituent selected from R₄.
 4. The compound ofclaim 1 wherein R₁ is selected from the group consisting of hydrogen,benzyl, phenylpropyl and benzofurylmethyl, 5 wherein phenyl, the phenylportion of benzyl and the benzofuryl portion of benzofurylmethyl areoptionally substituted with a substituent selected from R₄.
 5. Thecompound of claim 1 wherein R₂ is hydrogen.
 6. The compound of claim 1wherein R₃ is aryl(C₂₋₈)alkenyl, wherein aryl is optionally substitutedwith one to three substituents independently selected from halogen. 7.The compound of claim 1 wherein R₃ is a substituent independentlyselected from the group consisting of phenethenylene andphenylpropenylene, wherein phenyl is optionally substituted with one tothree substituents independently selected from the group consisting ofchlorine and fluorine.
 8. The compound of claim 1 wherein R₃ isphenethenylene, wherein phenyl is substituted with one to threesubstituents selected from chlorine.
 9. The compound of claim 1 whereinR₄ is selected from the group consisting of hydroxy, di(C₁₋₄alkyl)amino,C₁₋₈alkoxy, carboxy, carboxy(C₁₋₈)alkoxy, aryl(C₁₋₈)alkoxy,C₁₋₈alkoxycarbonyl, C₁₋₈alkoxycarbonyl(C₁₋₈)alkoxy, aminocarbonyl,(C₁₋₈alkyl)aminocarbonyl, (carboxy(C₁₋₈)alkyl)aminocarbonyl andC₁₋₈alkoxycarbonyl(C₁₋₈)alkyl)aminocarbonyl.
 10. The compound of claim 1wherein R₄ is selected from the group consisting of hydroxy, carboxy,carboxy(C₁₋₈)alkoxy, C₁₋₈alkoxycarbonyl, C₁₋₈alkoxycarbonyl(C₁₋₈)alkoxy,aminocarbonyl, (carboxy(C₁₋₈)alkyl)aminocarbonyl andC₁₋₈alkoxycarbonyl(C₁₋₈)alkyl)aminocarbonyl.
 11. The compound of claim 1wherein R₄ is selected from the group 5 consisting of hydroxy, carboxy,carboxymethoxy, methoxycarbonyl, aminocarbonyl,(carboxymethylene)aminocarbonyl andmethoxycarbonylmethylene)aminocarbonyl.
 12. The compound of claim 1wherein G is selected from the group 10 consisting of hydrogen, halogen,hydroxy, C₁₋₄alkyl, C₁₋₈alkoxy, aryl, aryloxy, aryl(C₁₋₈)alkyl,aryl(C₁₋₈)alkoxy, amino and trihalo(C₁₋₈)alkyl.
 13. The compound ofclaim 1 wherein G is hydrogen.
 14. The compound of claim 1 of theformula:

wherein R₄ is selected from the group consisting of R₄ 4—OH; 4—CO₂CH₃;3—CO₂CH₃; 4—CO₂H; 3—CO₂H; 3—OH; 3—OCH₂CO₂CH₃; 4—CONH₂; 4—CONHCH₂CO₂CH₃;3—OCH₂CO₂H; 4—CONHCH₂CO₂H; 3—CONHCH₂CO₂CH₃; 3—CONHCH₂CO₂H; 3—CONH₂;4—NHC(═NH)NH₂; and, 3—CO₂CH₃-4—OH; and pharmaceutically acceptable saltsthereof.
 15. The compound of claim 1 of the formula:

wherein R₁ is: R₁ PhCH₂; H; and, 2-benzofuranylCH₂; and pharmaceuticallyacceptable salts thereof.
 16. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier.
 17. Aprocess for preparing a pharmaceutical composition comprising mixing acompound of claim 1 and a pharmaceutically acceptable carrier.
 18. Amethod for treating a serine protease or dual-serine protease mediateddisorder in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound of claim
 1. 19.The method of claim 18 wherein the disorder is mediated by selectiveinhibition of a serine protease.
 20. The method of claim 19 wherein theserine protease is selected from the group consisting of Factor Xa andtryptase.
 21. The method of claim 18 wherein the disorder is mediated bydual inhibition of at least two serine proteases.
 22. The method ofclaim 21 wherein the serine protease is selected from the groupconsisting of at least Factor Xa and tryptase.
 23. The method of claim18 wherein the serine protease or dual-serine protease mediated disorderis selected from the group consisting of thrombotic disorders, arterialthrombosis, venous thrombosis, restenosis, hypertension, heart failure,arrhythmia, myocardial infarction, acute myocardial infarction,reocclusion following thrombolytic therapy, reocclusion followingangioplasty, inflammation, angina, unstable angina, stroke,atherosclerosis, ischemic conditions, neurodegenerative disorders(associated with thrombotic or ischemic conditions), asthma andinflammatory bowel syndrome.
 24. The method of claim 18 wherein thetherapeutically effective amount of the compound of claim 1 is fromabout 0.001 mg/kg/day to about 300 mg/kg/day.